The abuse of 3,4-methylenedioxymethamphetamine (MDMA), or ecstasy, continues to increase, especially on college campuses. During the previous grant period we an others have investigated the neurochemical alterations that occur after one large or repeated smaller doses of MDMA. Profound decreases in tryptophan hydroxylase (TPH) activity and in 5-hydroxytryptamine (5HT) and its metabolite, 5-hydroxyindoleacetic acid (5HIAA), have been observed in several brain regions; these changes in serotonergic parameters persist for long periods of time after discontinuning the drug. In the current proposal, the mechanisms(s) by which MDMA and its congeners cause their effects will be investigated. The possible role of excitatory amino acids in the MDMA-induced effects will be determined. Whether dopamine (DA) and/or GHT are involved in the MDMA- induced effects will be assessed by techniques previously employed in our investigation of methamphetamine and its analogs; in this part of the study we will determine the MDMA-induced changes in brain neuropeptide concentrations. The importance of oxidative stress and the possible role of adrenal steroids in the response will be explored. The development of tolerance to MDMA and its congeners will also be studied. Finally, the neurochemical effects of 4-methylaminorex (UrEA), an analog that has recently appeared on the street, will be investigated. Not only will these studies provide information on the neurochemical effects of abuse of MDMA and similar designer drugs, but the interrelationship between the dopaminergic, serotonergic and neuropeptide systems will also be investigated.